Optimization of chemotherapy administration for clinical 41.8 degrees C whole body hyperthermia.
Preclinical data is consistent with the concept that the timing of chemotherapy during radiant heat-whole body hyperthermia (WBH) should affect therapeutic index. In order to test this hypothesis, a controlled clinical investigation was initiated. Patients received carboplatin (CBDCA) on an early or late schedule with respect to achieving target temperature (i.e. 41.8 degrees C) in alternating treatment cycles. The first cycle was randomized between patients regarding the early or late schedule for two planned sets per patient (i.e. four cycles). Ifosfamide, etoposide and granulocyte colony stimulating factor were delivered during all cycles with a standardized schedule. A total of 53 cycles involving 17 patients were analyzed. Detailed toxicity evaluation (i.e. delay in therapy secondary to thrombocytopenia, need for platelet transfusions, and days of hospitalization) taken collectively demonstrated a statistically and clinically significant advantage to delivering CBDCA 10 min after target temperature, during the plateau phase of WBH.


Dolichol content in isolated sinusoidal liver cells after in vivo chronic treatment with thioacetamide.
The content of dolichol, an isoprenoid present in all biological membranes, was determined in isolated sinusoidal liver cells after treatment of rats for 2 and 4 months with a low dosage of the hepatotoxin thioacetamide. The significant decrease in dolichol observed in hepatocytes after 2 months might be explained by peroxidation of the isoprenoid. At the same time point, retinol was retained, and decreased only after 4 months of treatment. After 4 months of treatment therefore both lipids decreased. In a subfraction of hepatic stellate cells, Ito-1 cells, the main storage site of vitamin A, dolichol decreased significantly only after 4 months. A remarkable difference from hepatocytes is that in Ito-1 cells retinol content significantly decreased after 2 months of treatment. In another subfraction, Ito-2 cells, the content of the two isoprenoids decreased in parallel. This heterogeneous subfraction might represent those transitional hepatic stellate cells that, while losing retinol, are in the process of differentiating into myofibroblasts secreting extracellular matrix components. In Kupffer cells and sinusoidal endothelial cells, impairment of dolichol might be observed later, only after 4 months of treatment, while retinol decreases uniformly over time. Starting after two months of treatment, the decrease of dolichol and the increase of retinol in hepatocytes, at the same time as retinol decreases in hepatic stellate cells, might be taken as an early index of incipient liver injury due to thioacetamide. This hypothesis is discussed with regard to a role of dolichol in the modulation of membrane fluidity for intracellular and intercellular retinol transport.


Advancements and opportunities in sterilisation.
Radiation sterilisation often significantly degrades polymers. This article reports on a study that compares materials degradation after sterilisation by gamma and electron beam (E-beam). Also, in a discussion of the mechanisms of thermal processing by steam autoclave, ways to enhance product quality are presented.


How Does Awareness Modulate Goal-Directed and Stimulus-Driven Shifts of Attention Triggered by Value Learning?
In order to behave adaptively, attention can be directed in space either voluntarily (i.e., endogenously) according to strategic goals, or involuntarily (i.e., exogenously) through reflexive capture by salient or novel events. The emotional or motivational value of stimuli can also strongly influence attentional orienting. However, little is known about how reward-related effects compete or interact with endogenous and exogenous attention mechanisms, particularly outside of awareness. Here we developed a visual search paradigm to study subliminal value-based attentional orienting. We systematically manipulated goal-directed or stimulus-driven attentional orienting and examined whether an irrelevant, but previously rewarded stimulus could compete with both types of spatial attention during search. Critically, reward was learned without conscious awareness in a preceding phase where one among several visual symbols was consistently paired with a subliminal monetary reinforcement cue. Our results demonstrated that symbols previously associated with a monetary reward received higher attentional priority in the subsequent visual search task, even though these stimuli and reward were no longer task-relevant, and despite reward being unconsciously acquired. Thus, motivational processes operating independent of conscious awareness may provide powerful influences on mechanisms of attentional selection, which could mitigate both stimulus-driven and goal-directed shifts of attention.


Effectiveness of brief group intervention in the harmful alcohol use in primary health care.
To verify the effectiveness of brief group intervention, performed by nurses, in reducing the hazardous or harmful alcohol use in users of a primary health care service. Clinical and randomized trial with follow-up of three months. The sample had 180 individuals with a pattern of hazardous or harmful alcohol use, recruited in a Basic Health Unit in the city of São Paulo. A sociodemographic questionnaire and the Alcohol Use Disorders Identification Test (Audit) were applied. The experimental group underwent the Brief Group Intervention, which had four group sessions, with weekly meetings. The control group received an information leaflet about issues related to alcohol consumption. Both groups participated in the follow-up of three months. The linear mixed model was used for data analysis, in which a 5% significance level was adopted. Forty-four individuals under hazardous or harmful alcohol use completed all phases of the research. The experimental group had a statistically significant reduction (p < 0.01) of about 10 points in Audit score after the brief group intervention [before BGI = 15.89 (SD = 6.62) - hazardous use; after BGI = 6.40 (SD = 5.05) - low hazardous use] maintaining the low hazardous use in follow-up [6.69 (SD = 6.38) - low hazardous use]. The control group had a statistically significant reduction (p ≤ 0.01) of about three points in Audit score [before BGI = 13.11 (SD = 4.54) - hazardous use; after BGI = 9.83 (SD = 5.54) - hazardous use] and in follow-up presented the mean score of 13.00 (SD = 5.70), indicative of hazardous use. Differences between the two groups (experimental group versus control group) in reduction of consumption were statistically significant (p ≤ 0.01). Our evidence showed that the brief group intervention performed by the nurse in the primary health care context was effective to reduce alcohol consumption in individuals with patterns of hazardous or harmful use.


Pressure tuning of an ionic insulator into a heavy electron metal: an infrared study of YbS.
Optical conductivity [sigma(omega)] of YbS has been measured under pressure up to 20 GPa. Below 8 GPa, sigma(omega) is low since YbS is an insulator with an energy gap between a fully occupied 4f state and an unoccupied conduction (c) band. Above 8 GPa, however, sigma(omega) increases dramatically, developing a Drude component due to heavy carriers and characteristic infrared peaks. It is shown that increasing pressure has caused an energy overlap and hybridization between the c band and 4f state, thus driving the initially ionic and insulating YbS into a correlated metal with heavy carriers.


The novel chloroplast outer membrane kinase KOC1 is a required component of the plastid protein import machinery.
The biogenesis and maintenance of cell organelles such as mitochondria and chloroplasts require the import of many proteins from the cytosol, a process that is controlled by phosphorylation. In the case of chloroplasts, the import of hundreds of different proteins depends on translocons at the outer and inner chloroplast membrane (TOC and TIC, respectively) complexes. The essential protein TOC159 functions thereby as an import receptor. It has an N-terminal acidic (A-) domain that extends into the cytosol, controls receptor specificity, and is highly phosphorylated in vivo However, kinases that phosphorylate the TOC159 A-domain to enable protein import have remained elusive. Here, using co-purification with TOC159 from Arabidopsis, we discovered a novel component of the chloroplast import machinery, the regulatory kinase at the outer chloroplast membrane 1 (KOC1). We found that KOC1 is an integral membrane protein facing the cytosol and stably associates with TOC. Moreover, KOC1 phosphorylated the A-domain of TOC159 in vitro, and in mutant koc1 chloroplasts, preprotein import efficiency was diminished. koc1 Arabidopsis seedlings had reduced survival rates after transfer from the dark to the light in which protein import into plastids is required to rapidly complete chloroplast biogenesis. In summary, our data indicate that KOC1 is a functional component of the TOC machinery that phosphorylates import receptors, supports preprotein import, and contributes to efficient chloroplast biogenesis.


Further evidence that anxiety and memory are regionally dissociated within the hippocampus.
The hippocampus has been implicated in the regulation of anxiety and memory processes. Nevertheless, the precise contribution of its ventral (VH) and dorsal (DH) division in these issues still remains a matter of debate. The Trial 1/2 protocol in the elevated plus-maze (EPM) is a suitable approach to assess features associated with anxiety and memory. Information about the spatial environment on initial (Trial 1) exploration leads to a subsequent increase in open-arm avoidance during retesting (Trial 2). The objective of the present study was to investigate whether transient VH or DH deactivation by lidocaine microinfusion would differently interfere with the performance of EPM-naive and EPM-experienced rats. Male Wistar rats were bilaterally-implanted with guide cannulas aimed at the VH or the DH. One-week after surgery, they received vehicle or lidocaine 2.0% in 1.0 microL (0.5 microL per side) at pre-Trial 1, post-Trial 1 or pre-Trial 2. There was an increase in open-arm exploration after the intra-VH lidocaine injection on Trial 1. Intra-DH pre-Trial 2 administration of lidocaine also reduced the open-arm avoidance. No significant changes were observed in enclosed-arm entries, an EPM index of general exploratory activity. The cautious exploration of potentially dangerous environment requires VH functional integrity, suggesting a specific role for this region in modulating anxiety-related behaviors. With regard to the DH, it may be preferentially involved in learning and memory since the acquired response of inhibitory avoidance was no longer observed when lidocaine was injected pre-Trial 2.


Supramolecular photochemical synthesis of an unsymmetrical cyclobutane.
2-styrylbenzothiazole (1) and cinnamic acid (2) derivatives containing 15-crown-5 ether moieties form a supramolecular assembly in the presence of Ba(2+) cations in acetonitrile. The assembly is stabilized by hydrogen bonding between the heterocyclic N atom of 1 and the proton of the carboxylic group of 2, by sandwich Ba(2+) complex formation between the crown ether moieties of 1 and 2, and by pi-pi stacking interactions. Irradiation of solutions containing these supramolecular complexes leads to highly specific formation of an unsymmetrical cycloadduct. This investigation provides an interesting example of supramolecular control of [2 + 2]-photocyclization in solution.


Regulatory properties of yeast nitrate reductase in situ.
A simple and rapid procedure to make yeast cells permeable by agitating with toluene-ethanol, (TE) 1:4, v/v was developed. The permeated cells retained their ability to catalyze certain enzyme reactions. Temperature and duration of agitation during TE treatment played an important role in retention of the catalytic potential of permeated cells. The in situ assay using permeated cell preparations was more sensitive even in the absence of added cofactors than in the vitro assay in detecting assimilatory nitrate reductase (NAD(P)H:nitrate oxidoreductase, EC 126.96.36.199) (NAR) activity in Candida utilis. Using in situ assay technique, different mechanisms regulating the biosynthesis of NAR in C. utilis were investigated. Nitrogen starvation did not lead to derepression of NAR. NO3-ions were absolutely essential for induction and maintenance of high levels of NAR activity. Cells grown on ammonium nitrate possessed relatively lower levels of NAR. Kinetics of NAR induction were followed as a function of time and inducer concentration. The influence of various cations on the induction of NAR by nitrate was investigated. A wide range of D-amino acids induced NAR synthesis. Of 22 L-amino acids tested only phenylalanine induced significant levels of NAR. Various intermediates of the pathway of nitrate reduction influenced the rate of NAR induction. There was a rapid disappearance of in vivo activity of the enzyme of induced yeast cells on nitrogen starvation, and the rate of loss was accelerated by the presence of NH4+.


Current models of mammalian target of rapamycin complex 1 (mTORC1) activation by growth factors and amino acids.
Mammalian target of rapamycin (mTOR), which is now referred to as mechanistic target of rapamycin, integrates many signals, including those from growth factors, energy status, stress, and amino acids, to regulate cell growth and proliferation, protein synthesis, protein degradation, and other physiological and biochemical processes. The mTOR-Rheb-TSC-TBC complex co-localizes to the lysosome and the phosphorylation of TSC-TBC effects the dissociation of the complex from the lysosome and activates Rheb. GTP-bound Rheb potentiates the catalytic activity of mTORC1. Under conditions with growth factors and amino acids, v-ATPase, Ragulator, Rag GTPase, Rheb, hVps34, PLD1, and PA have important but disparate effects on mTORC1 activation. In this review, we introduce five models of mTORC1 activation by growth factors and amino acids to provide a comprehensive theoretical foundation for future research.


Association between Self-reported Snoring and Prediabetes among Adults Aged 40 Years and Older without Diabetes.
Several previous studies have shown that snoring is associated with glucose metabolism and the development of diabetes, but rare study has shown the association between snoring frequency and prediabetes, particularly in China. We hypothesized that individuals who snore might have a higher risk of prediabetes. This study aimed to investigate the association between self-reported snoring and prediabetes in a Chinese population. A cross-sectional study was performed in three large communities of Beijing from December 2011 to August 2012 by recruiting individuals aged ≥40 years old. All participants were requested to complete a detailed questionnaire and undergo anthropometric measurements. A 75 g oral glucose tolerance test was performed in individuals without diabetes. Blood samples of all participants were collected; blood glucose and blood fat levels were measured. Multivariate logistic regression models were built to assess the association between snoring frequency and prediabetes. A total of 13,592 participants (female: 66.56%; mean age: 56.8 ± 7.9 years; mean body mass index: 25.5 ± 3.4 kg/m2) were included in the final analysis. Of these, 30.9% were diagnosed with prediabetes, while 41.3% and 25.4% had occasional and habitual snoring, respectively. Habitual snoring was associated with an increased risk of prediabetes (odds ratio [OR]: 1.3, 95% confidence interval [CI]: 1.1-1.4, P< 0.001), after adjusting for diabetes and sleep-related confounders in the multivariable models. Habitual snoring was also associated with isolated impaired fasting glucose (IFG; OR: 1.3, 95% CI: 1.0-1.6; P< 0.001) and isolated impaired glucose tolerance (IGT; OR: 1.3, 95% CI: 1.2-1.5; P< 0.001), but not IFG + IGT (OR: 1.1, 95% CI: 0.9-1.4; P = 0.281). When stratified by total cholesterol (TC) levels, this association between habitual snoring and prediabetes was observed only in individuals with TC <5.6 mmol/L (OR: 1.4, 95% CI: 1.2-1.6; P< 0.001). Habitual snoring is associated with prediabetes, but only in individuals with TC <5.6 mmol/L. Further prospective studies are needed to confirm this finding.


Marked lymphovascular invasion, progesterone receptor negativity, and high Ki67 labeling index predict poor outcome in breast cancer patients treated with endocrine therapy alone.
Whether postoperative chemotherapy should be added to endocrine therapy or not is an important issue in patients with hormone receptor-positive and human epidermal growth factor receptor (HER)2-negative breast cancer. To identify patients who should be treated with additional chemotherapy, prognostic factors were investigated in breast cancer patients postoperatively treated with endocrine therapy alone. Tumor samples and clinicopathological data were collected from patients who underwent curative surgery and were postoperatively treated with endocrine therapy alone between 1999 and 2003 in three different institutes. Expression levels of estrogen receptor (ER), progesterone receptor (PgR), and HER2 in primary tumors were centrally retested. Patients with ER-negative and/or HER2-positive tumors and/or with unknown nodal status were excluded from the study subjects. Immunohistochemical analysis of Ki67, HER1, insulin-like growth factor-1 receptor, and aldehyde dehydrogenase-1 was also performed. Prognostic factors were investigated by univariate and multivariate analyses. A total of 261 patients were the subjects of this study. The median age was 59 years old, the mean tumor size was 1.9 cm, the node-positive rate was 20 %, and 65 % received tamoxifen alone. Distant metastases were observed in 11 patients at a median follow-up of 98 months, and four patients had died of breast cancer at a median follow-up of 99 months. Univariate analysis showed that marked lymphovascular invasion (LVI), PgR negativity, high Ki67 labeling index (LI), and high nuclear grade were significantly worse prognostic factors for distant metastasis. Multivariate analysis revealed that marked LVI [hazard ratio (HR) 21.8] and PgR negativity (HR 10.3) were independently worse prognostic factors for distant metastasis, respectively. Multivariate analysis also revealed that marked LVI (HR 287.3), PgR negativity (HR 25.1), and high Ki67 LI (HR 19.6) were independently worse prognostic factors for breast cancer-specific death, respectively. The results of this multi-institute cohort study indicated that endocrine therapy alone could not prevent distant metastasis in breast cancer patients with PgR-negative tumors and/or with tumors showing marked LVI or high cell proliferation. These patients may need postoperative adjuvant chemotherapy in addition to endocrine therapy.


Reversibly Reconfigurable Colloidal Plasmonic Nanomaterials.
With their unique ability to concentrate and scatter light, plasmonic nanomaterials have been the focus of tremendous synthesis and characterization efforts in the past two decades. Recently, the topic of reversibly reconfigurable plasmonic nanomaterials has become an intensive research area offering the opportunity to reconfigure the optical, mechanical, electronic, and catalytic properties of materials with promising applications in fields ranging from biosensors to nanorobotics and energy. This Perspective discusses the state of the art in the fabrication and application of reversibly reconfigurable colloidal plasmonic nanomaterials based on the actuation of interparticle couplings and explores some promising directions for future research ranging from direction control, two-dimensional materials, and the incorporation of feedback mechanisms for designing robust responses.


Polymer-mediated flocculation of transient CHO cultures as a simple, high throughput method to facilitate antibody discovery.
Most biopharmaceutical drugs, especially monoclonal antibodies (mAbs), bispecific antibodies (BsAbs) and Fc-fusion proteins, are expressed using Chinese Hamster Ovary (CHO) cell lines. CHO cells typically yield high product titers and high product quality. Unfortunately, CHO cell lines also generate high molecular weight (HMW) aggregates of the desired product during cell culture along with CHO host cell protein (HCP) and CHO DNA. These immunogenic species, co-purified during Protein A purification, must be removed in a multi-step purification process. Our colleagues have reported the use of a novel polymer-mediated flocculation step to simultaneously reduce HMW, HCP and DNA from stable CHO cell cultures prior to Protein A purification. The objective of this study was to evaluate this novel "smart polymer" (SmP) in a high throughput antibody discovery workflow using transiently transfected CHO cultures. SmP treatment of 19 different molecules from four distinct molecular categories (human mAbs, murine mAbs, BsAbs and Fabs) with 0.1% SmP and 25 mM stimulus resulted in minimal loss of monomeric protein. Treatment with SmP also demonstrated a variable, concentration-dependent removal of HMW aggregates after Protein A purification. SmP treatment also effectively reduced HCP levels at each step of mAb purification with final HCP levels being several fold lower than the untreated control. Interestingly, SmP treatment was able to significantly reduce high concentrations of artificially spiked levels of endotoxin in the cultures. In summary, adding a simple flocculation step to our existing transient CHO process reduced the downstream purification burden to remove impurities and improved final product quality. © 2017 American Institute of Chemical Engineers Biotechnol. Prog., 33:1393-1400, 2017.


Rural-urban differences in sociodemographic, social network and lifestyle factors related to mortality of middle-aged Japanese men from the Komo-Ise cohort study.
To examine rural-urban differences in the relationships of sociodemographic, social network, and lifestyle factors to mortality in middle-aged men, we used the data from a community based prospective cohort study, the Komo-Ise study. The subjects were all men aged 40-69 years living in Komochi Village, the rural group (n=2,295), or the downtown district of Isesaki City, the urban group (n=3,334), as of 1993. They completed a self-administered questionnaire in 1993 and were followed for all-cause deaths until 2000. The Cox proportional hazards model was used to compute relative risks (RRs) with 95% confidence intervals (CIs). Low educated men and men without a spouse in the rural group had an increased risk of mortality (RR=4.4; 95%CI: 1.1-18.2, RR=2.4; 95%CI: 1.2-4.5). Men who did not enjoy good fellowship with their neighbors in the rural group had a decreased risk of mortality (RR=0.58; 95%CI: 0.35-0.97). Mortality risks were significantly higher in urban men not participating in hobbies, club activities or community groups (RR=1.6; 95%CI: 1.1-2.4). These variables remained significant risk factors, even after controlling for all sociodemographic, social network, lifestyle, and health status variables. Educational level, marital status and relation to neighborhoods showed significant rural-urban differences.


Breakfast glycemic index affects subsequent daily energy intake in free-living healthy children.
Experimental studies have reported that the effect of a meal's glycemic index (GI) on subsequent energy intake depends on the timing of the subsequent meal. We examined whether the timing of the next meal after breakfast modifies the effect of the breakfast GI (GI(br)) on subsequent daytime energy intake of healthy free-living children. Analyses included 381 participants of the DOrtmund Nutritional and Anthropometrical Longitudinally Designed (DONALD) Study who had provided weighed dietary records at ages 2, 4-5, and 7 y. At all ages, among children who consumed their next meal in the early postprandial phase (after 3-4 h), children with a lower GI(br) consumed more calories throughout the remainder of the day than did children with a higher GI(br), independent of major dietary confounders. For the age groups 2, 4-5, and 7 y, energy intakes in tertiles 1 and 3 were 785 kcal (95% CI: 743-830 kcal) and 717 kcal (678-758 kcal), P for trend = 0.2; 993 kcal (941-1047 kcal) and 949 kcal (900-1000 kcal), P for trend = 0.05; 1255 (1171-1344) and 1166 (1090-1247 kcal), P for trend = 0.03, respectively. Conversely, among children consuming their next meal in the late postprandial phase (>3-4 h), subsequent daytime energy intake was not associated with GI(br). This study confirms differential early and late postprandial effects of the GI(br) on subsequent daytime energy intake for free-living children at different ages. Interestingly, the apparent short-term satiating effect of a higher GI(br), in particular, persisted throughout the day, if a second breakfast was consumed midmorning.


Mycobacteremia from Crushed Hydromorphone Tablet Injection.
Mycobacterium abscessus is a fast growing, non-tubercular mycobacterium (NTM) found in water. NTM bacteremia is usually seen in immunocompromised patients who have intravascular catheters. Mycobacterium abscessus bacteremia is often caused by exposure to contaminated water supply in hemodialysis units. A 28-year-old female with poorly controlled diabetes mellitus, end stage renal disease (on hemodialysis via Ash catheter), and recurrent deep vein thrombosis presented to the hospital with proximal right leg deep vein thrombosis. On day nine of admission, the patient spiked a fever. Blood cultures revealed Mycobacterium abscessus bacteremia. The patient was observed to be crushing oral hydromorphone and injecting it into her ash catheter using needles retrieved from the sharps disposal container in her room. Although the Michigan Automated Prescription System (MAPS) report for narcotic abuse was unremarkable, a thorough review of her electronic medical chart revealed multiple hospitalizations with drug seeking behavior. This is the first reported case of crushed oral opioid injection resulting in mycobacteremia. Injecting crushed opioids has become more prevalent. Many opioid abusers resort to injecting them in order to achieve the psychotropic effects quicker. A heightened awareness about nontraditional modes of prescription drug abuse and surveillance by prescribers is necessary. This case raises an ethical question: should such patients be prescribed narcotics in the future, as the outcome of injecting oral medications can be fatal.


Effects of an Elastic Hamstring Assistance Device During Downhill Running.
The purpose of this study was to determine the appropriateness of using an elastic hamstring assistance device to reduce perceived levels of soreness, increase isometric strength, increase passive range of motion, and decrease biomarkers of muscle damage after eccentric exercise, specifically, downhill running This study was conducted in a university exercise physiology laboratory placing sixteen apparently healthy males (X = 21.6 ± 2.5 years) into two groups using a pre-test/post-test design. Pre-intervention measures taken included participants' body height, body mass, body fat, capillary blood samples, VO2max, isometric hamstring strength at 45 and 90 degrees of flexion and passive hamstring range of motion. Post-intervention measures included blood biomarkers, passive range of motion, the perceived level of soreness and isometric strength. An analysis of normality of data was initially conducted followed by multivariate analysis of variance (MANOVA) of hamstring strength at 45 and 90 degrees of flexion, blood myoglobin and passive range of motion of the hamstrings. Statistically significant changes were noted in subject-perceived muscle soreness and isometric strength at 90 degrees at the 24-hour post-exercise trial measure between the two groups. Results would suggest the findings could be explained by the decrease in muscle soreness from utilizing the device during the exercise trial. Further research should be conducted to address sample size issues and to determine if the results are comparable on different surfaces.


Taxonomic diversity of microbial communities in sub-seafloor hydrothermal sediments of the active Santorini-Kolumbo volcanic field.
Active hydrothermal vents of volcanic origin provide a remarkable manifestation of life on Earth under extreme conditions, which may have consequences for our understanding of habitability on other terrestrial bodies as well. Here, we performed for the first time Illumina sequencing of bacterial and archaeal communities on sub-seafloor samples collected from the Santorini-Kolumbo volcanic field. A total of 19 (3-m long) gravity corers were collected and processed for microbial community analysis. From a total of 6,46,671 produced V4 sequences for all samples, a total of 10,496 different Operational Taxonomic Units (OTUs) were identified that were assigned to 40 bacterial and 9 archaeal phyla and 14 candidate divisions. On average, the most abundant phyla in all samples were Chloroflexi (Chloroflexota) (24.62%), followed by Proteobacteria (Pseudomonadota) (11.29%), Firmicutes (Bacillota) (10.73%), Crenarchaeota (Thermoproteota) (8.55%), and Acidobacteria (Acidobacteriota) (8.07%). At the genus level, a total of 286 known genera and candidate genera were mostly dominated by members of Bacillus, Thermoflexus, Desulfatiglans, Pseudoalteromonas, and Pseudomonas. In most of the stations, the Chao1 values at the deeper layers were comparable to the surface sediment samples denoting the high diversity in the subsurface of these ecosystems. Heatmap analysis based on the 100 most abundant OTUs, grouped the sampling stations according to their geographical location, placing together the two hottest stations (up to 99°C). This result indicates that this specific area within the active Kolumbo crater create a distinct niche, where microorganisms with adaptation strategies to withstand heat stresses can thrive, such as the endospore-forming Firmicutes.


Integrative approach reveals two new species of Obama (Platyhelminthes: Tricladida) from the South-Brazilian Atlantic Forest.
The genus Obama Carbayo et al., 2013 includes 38 species, being the most species-rich within Geoplaninae. Species of this genus show a similar anatomy regarding their copulatory apparatus, which may hinder species differentiation. In this study, we describe two new species, presenting a marbled colour pattern, found in two different phytophysionomies of the Atlantic Forest, namely Semi-deciduous Forest and Araucaria Forest. Both species can be distinguished from their congeners, as well from each other, by colour pattern and eye arrangement combined with characteristics of the pharynx, penis papilla and prostatic vesicle, confirmed by molecular analyses from cytochrome c oxidase subunit I gene (COI). Phylogenetic analyses suggest that both species herein studied are closely related to another species that occurs in areas of Araucaria Forest (O. maculipunctata). Results also indicate the need to use at least 600 bp of the gene COI in the definitions of interspecific divergences and for species delineation, at least for the genus Obama.


Medical neurobiology: do we teach neurobiology in a format that is relevant to the clinical setting?
During a period of unprecedented growth in technology that allows imaging of the body in elegant detail, anatomy as a discipline has, in some instances, become marginalized. This may be seen in a reduction of time allotted to anatomy, reduction or elimination of laboratory experiences, or shifting of anatomy teaching to clinical departments. One potential cause of this marginalization is the fact that anatomy is frequently taught in a format that is not useful in, or even applicable to, the clinical setting. At the University of Mississippi Medical Center, the Medical Neurobiology course stresses the functional anatomy of the brain, especially the brainstem, in a format that is directly transferable to the clinical setting. These approaches include (1) using a small neurology book as one of the required texts in the course; (2) extensive use of magnetic resonance imaging (MRI) and computed tomography (CT) as an integral part of the instructional approach; (3) teaching external and internal anatomy of the brain, particularly the brainstem and spinal cord, in a "clinical orientation" that reflects how these central nervous system (CNS) regions are viewed in the clinical setting; (4) teaching nuclei and tracts in images of stained sections and correlating this information with comparable MRI and CT images; and (5) using a large series (75 images) of vascular drawings and clinical cases, all in clinical orientation. The clinical applicability of the basic science information, therefore, is continuously reinforced and extended. It is suggested that teaching anatomy and anatomical concepts in formats that are more obviously useful in, and applicable to, the clinical setting will enhance the value of this basic science in the medical curriculum.


Comparative genomic hybridization as part of a new diagnostic strategy in childhood hyperdiploid acute lymphoblastic leukemia.
The detailed definition of karyotype changes associated with hyperdiploid acute lymphoblastic leukemia (ALL) is a precondition for their exploitation in minimal residual disease studies with fluorescence in situ hybridization analysis (FISH). In addition, certain karyotype patterns may have different prognostic implications. We have therefore used comparative genomic hybridization (CGH) to analyze the quantitative karyotype abnormalities in 14 cases of hyperdiploid ALL and correlated the results with those obtained by flow cytometry and conventional cytogenetic analyses. Despite an overall good agreement between the karyotypes obtained by classical banding techniques and CGH, we came across at least one karyotype discrepancy per case. Clarification of the discordant findings with fluorescence in situ hybridization (FISH) showed that all stem lines had been correctly defined by CGH. In eight cases, however, cytogenetic analyses revealed structural abnormalities that were undetectable by CGH. The other discrepancies were mainly due to a cytogenetic misinterpretation of similar sized and shaped chromosomes. Based on these findings we present a new diagnostic strategy for childhood ALL that includes flow cytometry and classical cytogenetics as well as CGH for the analysis of aneuploid cases and FISH to resolve the unavoidable discrepancies.


Refractory celiac disease type 2: how to diagnose and treat?
Refractory celiac disease is an uncommon condition which might be associated to poor prognosis. It is often treated with immunosuppressive medications, with poor results. It is divided in type 1 and type 2, the latter carrying a high risk for lymphoma and mortality. A case of a 41 year old female patient with refractory celiac disease type 2 is reported. She was treated with oral budesonide for six months, achieving histological remission.


cAMP response element-binding protein interacts with and stimulates the proteasomal degradation of the nuclear receptor coactivator GRIP1.
The glucocorticoid receptor interacting protein (GRIP1) belongs to the p160 steroid receptor coactivator family that plays essential roles in nuclear receptor-dependent transcriptional regulation. Previously, we reported that the cAMP-dependent protein kinase (PKA) induces ubiquitination leading to degradation of GRIP1. Here we show that the cAMP response element-binding protein (CREB) downregulates GRIP1 and is necessary for the PKA-stimulated degradation of GRIP1, which leads to changes in the expression of a subset of genes regulated by estrogen receptor-α in MCF-7 breast cancer cells. Our data of domain-mapping and ubiquitination analyses suggest that CREB promotes the proteasomal breakdown of ubiquitinated GRIP1 through 2 functionally independent protein domains containing amino acids 347 to 758 and 1121 to 1462. We provide evidence that CREB interacts directly with GRIP1 and that CREB Ser-133 phosphorylation or transcriptional activity is not required for GRIP1 interaction and degradation. The basic leucine zipper domain (bZIP) of CREB is important for the interaction with GRIP1, and deletion of this domain led to an inability to downregulate GRIP1. We propose that CREB mediates the PKA-stimulated degradation of GRIP1 through protein-protein interaction and stimulation of proteasomal degradation of ubiquitinated GRIP1.


A Novel Neural Network for Remote Sensing Image Matching.
Rapid development of remote sensing (RS) imaging technology makes the acquired images have larger size, higher resolution, and more complex structure, which goes beyond the reach of classical hand-crafted feature-based matching. In this paper, we propose a feature learning approach based on two-branch networks to transform the image matching task into a two-class classification problem. To match two key points, two image patches centered at the key points are entered into the proposed network. The network aims to learn discriminative feature representations for patch matching, so that more matching pairs can be obtained on the premise of maintaining higher subpixel matching accuracy. The proposed network adopts a two-stage training mode to deal with the complex characteristics of RS images. An adaptive sample selection strategy is proposed to determine the size of each patch by the scale of its central key point. Thus, each patch can preserve the texture structure around its key point rather than all patches have a predetermined size. In the matching prediction stage, two strategies, namely, superpixel-based sample graded strategy and superpixel-based ordered spatial matching, are designed to improve the matching efficiency and matching accuracy, respectively. The experimental results and theoretical analysis demonstrate the feasibility, robustness, and effectiveness of the proposed method.


Bumblebees land remarkably well in red-blue greenhouse LED light conditions.
Red-blue emitting LEDs have recently been introduced in greenhouses to optimise plant growth. However, this spectrum may negatively affect the performance of bumblebees used for pollination, because the visual system of bumblebees is more sensitive to green light than to red-blue light. We used high-speed stereoscopic videography to three-dimensionally track and compare landing manoeuvres of Bombus terrestris bumblebees in red-blue light and in regular, broad-spectrum white light. In both conditions, the landing approaches were interspersed by one or several hover phases, followed by leg extension and touchdown. The time between leg extension and touchdown was 25% (0.05 s) longer in red-blue light than in white light, caused by a more tortuous flight path in red-blue light. However, the total landing duration, specified as the time between the first hover phase and touchdown, did not differ between the light conditions. This suggests that the negative effects of red-blue light on the landing manoeuvre are confined to the final phase of the landing.This article has an associated First Person interview with the first author of the paper.


Transforming growth factor-beta-independent regulation of myogenesis by SnoN sumoylation.
Recent progress has been made on the role of oncoproteins c-Ski and related SnoN in the control of cellular transformation. c-Ski/SnoN potently repress transforming growth factor-beta (TGF-beta) antiproliferative signaling through physical interaction with signal transducers called Smads. Overexpression of c-Ski/SnoN also induces skeletal muscle differentiation, but how c-Ski/SnoN function in myogenesis is largely unknown. During our investigation on the role of sumoylation in TGF-beta signaling, we inadvertently found that SnoN is modified by small ubiquitin-like modifier-1 (SUMO-1). Here, we biochemically characterize SnoN sumoylation in detail and report the physiological function of the modification. Sumoylation occurs primarily at lysine 50 (Lys-50). PIAS1 and PIASx proteins physically interact with SnoN to stimulate its sumoylation, thus serving as SUMO-protein isopeptide ligases (E3) for SnoN sumoylation. SnoN sumoylation does not alter its metabolic stability or its ability to repress TGF-beta signaling. Notably, loss of sumoylation in the Lys-50 site (via a Lys-to-Arg point mutation) potently activates muscle-specific gene expression and enhances myotube formation. Our study suggests a novel role for SUMO modification in the regulation of myogenic differentiation.


Insertion of a testicular prosthesis at the time of radical orchiectomy for testicular cancer is safe in patients who will subsequently undergo chemotherapy or radiotherapy.
We aimed to assess the incidence of prosthesis-related complications in patients who received a testicular prosthesis at the time of radical orchiectomy for testicular cancer and were then treated with chemotherapy (ChT) or radiotherapy (RT). We reviewed the records of the patients who underwent radical orchiectomy at our Institute since 1999; we also retrieved data from patients who underwent surgery elsewhere and then received ChT or RT at our Institution since 1999. We used the chi-square test to evaluate differences in the incidence of prosthesis-related complications between the groups. We retrieved the records of 587 patients; 393 had a testicular prosthesis implanted. Median follow-up was 57.7 months. One hundred thirty-eight patients (35.11%) received ChT, 129 RT (38.82%) and 10 (2.55%) both ChT and RT; of them, 6 (4.34%), 8 (6.20%) and 0 reported problems respectively. Seven (6.03%) of the 116 patients (29.52%) who had no further treatment had complications. The incidence of complications was not significantly different between patients who had no further treatment versus patients who underwent ChT (p = .75) or RT (p = .83). Testicular prosthesis insertion at the time of radical orchiectomy is safe even in patients subsequently undergoing ChT or RT.


Iodoform toxicity following the use of B.I.P.P.: a potential hazard.
1. A case of severe iodoform toxicity is presented in a patient after a total maxillectomy whose cavity was packed with B.I.P.P. The patient subsequently recovered after removal of the B.I.P.P. pack. 2. A simple spectrophotometric method for measuring plasma iodine concentration is described. Plasma iodine determinations were carried out on the toxic patient and three others with iodoform containing packs. The concentrations found correspond well with the presence or absence of iodoform toxicity. 3. From the clinical and biochemical evidence presented we suggest that B.I.P.P. gauze is a satisfactory packing for small operative cavities, but that caution should be exercised if large cavities, such as those following maxillectomies, are to be packed with the material. Another iodoform containing mixture, Whitehead's varnish, is a safer alternative to B.I.P.P. gauze.


[Determination of ethyl methacrylate in workplace air by solvent desorption-gas chromatography].
Objective: To develop a solvent desorption-gas chromatography method for determination of ethyl methacrylate(EMA) in workplace air. Methods: EMA in workplace air was captured by charcoal tubes and desorbed with carbon disulfide, separated through capillary chromatographic column, and then analyzed by gas chromatography-flame ionization detector. Results: The linear ranges of EMA were 0.00-9108.00 mg/L, and the related coefficients were 0.999 96. The relative standard deviations(RSD) within the group were 0.55%-1.84%, and the RSD between the group were1.26%-3.30%. The average desorption efficiencies were 98.26%-100.58%. The average samplingefficiencies were 99.98%-100.00%. and the minimum detectable concentration and the minimum quantification concentration were respectively 0.03 mg/m(3) and 0.10 mg/m(3) per 3.00 L of air. The samples could be stored at room temperature for 7 days. Conclusion: This method could be used formonitoring of EMA in workplace air.


Agonist-induced desensitization of adenylyl cyclase in Y1 adrenocortical tumor cells.
Y1 adrenocortical tumor cells (Y1DS) and Y1 mutants resistant to ACTH-induced desensitization of adenylyl cyclase (Y1DR) were transfected with a gene encoding the mouse beta 2-adrenergic receptor (beta 2-AR). Transfectants expressed beta 2-ARs that were able to stimulate adenylyl cyclase activity and steroid biosynthesis. These transfectants were used to explore the basis for the DR mutation in Y1 cells. We demonstrate that beta-adrenergic agonists desensitize the adenylyl cyclase system in transfected Y1DS cells whereas transfected Y1DR cells are resistant to desensitization by beta-adrenergic agonists. The fate of the beta 2-ARs during desensitization was evaluated by photoaffinity labelling with [125I]iodocyanopindolol diazerine. Desensitization of Y1DS transfectants was accompanied by a modest loss in receptor density that was insufficient to account for the complete loss of responsiveness to beta-adrenergic agonists. The extent of receptor loss induced by beta-adrenergic agonists in Y1DR transfectants exceeded that in the Y1DS transfectants indicating that the mutation which protects Y1DR cells from agonist-induced desensitization is prior to receptor down-regulation in the desensitization pathway. From these results we infer that ACTH and isoproterenol desensitize adenylyl cyclase by a common pathway and that receptor loss is not a major component of the desensitization process in these cells.


Synergistic fibrinolysis: combined effects of plasminogen activators and an antibody that inhibits alpha 2-antiplasmin.
To improve the efficacy of plasminogen activators, we produced a monoclonal antibody (RWR) that inhibits human alpha 2-antiplasmin (alpha 2AP). In addition to inhibiting alpha 2AP in plasma, RWR binds to and inhibits fibrin cross-linked alpha 2AP and reproduces the "spontaneous" clot lysis that is the hallmark of human alpha 2AP deficiency. By inhibiting the inactivation of plasmin by alpha 2AP, RWR interacts synergistically with plasminogen activators to increase the potency (for 50% clot lysis) of urokinase by 80-fold, tissue plasminogen activator by 27-fold, and streptokinase by 20-fold. Yet, for a given amount of fibrinolysis, the combination of RWR and lower doses of plasminogen activator leads to less fibrinogen consumption than is obtained with higher, equipotent doses of plasminogen activator alone. These results suggest a strategy for increasing the efficacy of plasminogen activators. More generally, this approach to amplifying enzymatic activity by immunoneutralizing an inhibitor may be useful in other biologic processes that are rigidly governed by inhibitors.


GENETIC CORRELATIONS BETWEEN LIFE-HISTORY AND BEHAVIORAL TRAITS CAN CAUSE REPRODUCTIVE ISOLATION.
Reproductive isolation may often evolve as an indirect (pleiotropic) consequence of populations adapting to different environments or habitats. For example, niches that are temporally or seasonally offset can select for organisms with different developmental characteristics. These developmental differences can inadvertently cause reproductive isolation by a variety of means including shifts in mating activity patterns. Here, we show a genetic correlation between a life-history trait (developmental period) and a behavioral trait (time of mating) that causes significant premating isolation in the melon fly, Bactrocera cucurbitae (Diptera: Tephritidae). Fly lines selected for short and long developmental periods differ in their preferred times of mating during the evening. This difference translates into significant prezygotic isolation, as measured by mate choice tests. If the time of mating between two populations differed more than one hour, the isolation index was significantly higher than zero. These indicate that premating isolation can be established if the developmental period is divergently selected for. If such genetic correlations are ubiquitous in many organisms, multifarious divergent selection for life-history traits would often accelerate the evolution of reproductive isolation. We speculate that reproductive isolation may have been evolved via genetic correlations among time-related traits, for example, developmental period and time of mating, as in other organisms.


[Laparoscopy and digital subtraction angiography in the treatment of severe acute pancreatitis].
To study the effect of laparoscopy and digital subtraction angiography in the treatment of severe acute pancreatitis (SAP). Seventy-five SAP patients were randomly divided into tow groups: (1) Conventional treatment group (group A, n = 35); (2) Conventional treatment combined with laparoscopy and digital subtraction angiography treatment group (group B, n = 40). The clinical parameters and treatment results in the 2 groups were compared. After treatment, APACHE II score in group B was significantly lower than that in group A (P < 0.05). The functions of liver, renal and lung were recovered (P < 0.05, respectively), levels of serum TNF-alpha and IL-1 beta were significantly lower, but IL-10 significantly elevated (P < 0.05), the CT SPN was much lower (P < 0.05); rate of organ failure significantly decreased (P < 0.01), the successful rate of organ failure treatment was increased (P < 0.05); the in hospital mortality decreased (all P < 0.05). Laparoscopy and digital subtraction angiography in combination with conventional treatment for SAP significantly improves the outcome and decrease the mortality of SAP.


The Role of Rac GTPase in Dendritic Spine Morphogenesis and Memory.
The ability to form memories in the brain is needed for daily functions, and its impairment is associated with human mental disorders. Evidence indicates that long-term memory (LTM)-related processes such as its consolidation, extinction and forgetting involve changes of synaptic efficacy produced by alterations in neural transmission and morphology. Modulation of the morphology and number of dendritic spines has been proposed to contribute to changes in neuronal transmission mediating such LTM-related processes. Rac GTPase activity is regulated by synaptic activation and it can affect spine morphology by controlling actin-regulatory proteins. Recent evidence shows that changes in Rac GTPase activity affect memory consolidation, extinction, erasure and forgetting and can affect spine morphology in brain areas that mediate these behaviors. Altered Rac GTPase activity is associated with abnormal spine morphology and brain disorders. By affecting Rac GTPase activity we can further understand the roles of spine morphogenesis in memory. Moreover, manipulation of Rac GTPase activity may serve as a therapeutic tool for the treatment of memory-related brain diseases.


A case of fatal mitochondrial cardiomyopathy.
We report a case of mitochondrial cardiomyopathy in a Japanese boy who presented with severe cardiac heart failure and died 6 days after admission. The onset of mitochondrial cardiomyopathy often occurs very early in childhood and has a rapid downward course.


'Minimalist approach' for transcatheter mitral valve replacement using intracardiac echocardiography and conscious sedation: a case series.
Transcatheter aortic valve implantation operators have adapted to a less invasive technique by foregoing the use of general anaesthesia and transoesophageal echocardiography. This is known as a 'minimalist approach'. This approach has yet to be explored in transcatheter mitral valve replacement (TMVR). Two patients with high perioperative risk underwent TMVR using only monitored conscious sedation (CS) and intracardiac echocardiography (ICE). The patients were symptomatic and required treatment of severe mitral regurgitation and severe mitral stenosis in a mitral valve ring and prosthetic mitral valve, respectively. With the use of an antegrade transseptal approach, the procedure was conducted under CS using ICE only. After placement of the prosthetic mitral valve, the valve was assessed by advancing the ICE catheter through the interatrial septal defect and no significant paravalvular leak occurred. In one case, ad hoc treatment of right to left shunting was successfully pursued. Valve function was excellent immediately and at 24 h after implantation and resulted in significant haemodynamic improvement. With more TMVR cases being conducted, the 'minimalist approach' with CS and ICE may be considered in selected cases.


[Metastatic brain tumor originating from urachal carcinoma: case report].
The authors presented a patient with metastatic brain tumor originating from urachal carcinoma. A 64-year-old female was admitted to our hospital with complaints of memory disturbance, indifference and apathy of 3 months duration. Head CT and MRI on admission showed a round mass with perifocal edema in the right frontal lobe. After administration of Gd-DTPA, the mass lesion showed ringed enhancement effect. Pelvic MRI scan revealed a bladder tumor, which was diagnosed as urachal carcinoma. The brain lesion was suspected to have metasta sized metastatic from urachal carcinoma, and was excised by craniotomy. Histology of the brain tumor was identical to that of urachal carcinoma. Postoperatively the patient received local radiation therapy, but died of multiple metastasis to lung and local recurrence, 18 months later. Urachal carcinoma is an extremely rare tumor, comprising 0.17-0.34% of all bladder tumors. Though this rare tumor carries a poor prognosis, it may be effective for longer survival of a patient to treat the metastatic brain lesion with surgery and radiation.


Baroreflex Sensitivity Impairment During Hypoglycemia: Implications for Cardiovascular Control.
Studies have shown associations between exposure to hypoglycemia and increased mortality, raising the possibility that hypoglycemia has adverse cardiovascular effects. In this study, we determined the acute effects of hypoglycemia on cardiovascular autonomic control. Seventeen healthy volunteers were exposed to experimental hypoglycemia (2.8 mmol/L) for 120 min. Cardiac vagal baroreflex function was assessed using the modified Oxford method before the initiation of the hypoglycemic-hyperinsulinemic clamp protocol and during the last 30 min of hypoglycemia. During hypoglycemia, compared with baseline euglycemic conditions, 1) baroreflex sensitivity decreases significantly (19.2 ± 7.5 vs. 32.9 ± 16.6 ms/mmHg, P < 0.005), 2) the systolic blood pressure threshold for baroreflex activation increases significantly (the baroreflex function shifts to the right; 120 ± 14 vs. 112 ± 12 mmHg, P < 0.005), and 3) the maximum R-R interval response (1,088 ± 132 vs. 1,496 ± 194 ms, P < 0.001) and maximal range of the R-R interval response (414 ± 128 vs. 817 ± 183 ms, P < 0.001) decrease significantly. These findings indicate reduced vagal control and impaired cardiovascular homeostasis during hypoglycemia.


Using FADOF to eliminate the background light influence in ghost imaging.
The high solar background during the day adversely affects the long distance daytime operations of ghost imaging. It is extremely hard to distinguish the signal light from the background noise light after they are both converted to voltage or current signals by the bucket detector, so spectral filtering before the detector is quite important. In this work, a Faraday anomalous dispersion optical filter (FADOF) is used in eliminating the background light influence in ghost imaging. Results of lab experiment show that the background light noise tolerance of the ghost imaging with FADOF is at least 18 times bigger than that with a 10 nm optical filter. The method has simple structure, great performance and great algorithms compatibility.


Estimating vertical ground reaction forces during gait from lower limb kinematics and vertical acceleration using wearable inertial sensors.
One of the most important forces generated during gait is the vertical ground reaction force (vGRF). This force can be measured using force plates, but these can limit the scope of gait analysis. This paper presents a method to estimate the vGRF using inertial measurement units (IMU) and machine learning techniques. Four wearable IMUs were used to obtain flexion/extension angles of the hip, knee, and ankle joints, and an IMU placed over the C7 vertebra to measure vertical acceleration. We trained and compared the performance of two machine learning algorithms: feedforward neural networks (FNN) and random forest (RF). We investigated the importance of the inputs introduced into the models and analyzed in detail the contribution of lower limb kinematics and vertical acceleration to model performance. The results suggest that the inclusion of vertical acceleration increases the root mean square error in the FNN, while the RF appears to decrease it. We also analyzed the ability of the models to construct the force signal, with particular emphasis on the magnitude and timing of the vGRF peaks. Using the proposed method, we concluded that FNN and RF models can estimate the vGRF with high accuracy.


[Timing and methodology for the integrated geriatric assessment of the city geriatric center.]
A study was carried out on the timing of the complex geriatric assessment by nursing staff in the geriatric center of Saint Petersburg. 65 patients (women) were examined. It is concluded that the complex geriatric assessment can and should be carried out by the nursing staff, the duration of the complex geriatric assessment depends on the actual age, and the expression of frailty, the average time spent on it varies from 1 to 2 hours, the complex geriatric assessment should be carried out within 1 to 3 days.


The Korean American family: adolescents versus parents acculturation to American culture.
The goal of this cross-sectional study was to describe acculturation and characteristics of Korean American families. Self-reports were gathered from 106 families (105 mothers, 98 fathers, 106 adolescents) in the Midwest. Mothers, fathers, and adolescents maintained Korean cultural and linguistic characteristics while adopting some American cultural and linguistic features. The adoption of American culture and English was more evident among adolescents than their parents. The association between Korean American parents' acculturation attitudes and their characteristics were consistent with the acculturation framework. This information may provide basic understanding for health care providers who care for Korean American families.


[Recent advances of immunooncology in the treatment of solid tumours and haematological malignancies: the immune checkpoint inhibitors].
Cancer immunotherapy is coming of age, as outstanding results can be achieved in the therapy of cancer with poor prognosis by altering the patients' immune system and by promoting the immune response against tumours. Amongst immunotherapies, the immune checkpoint inhibitors (ICI) proved to be the most effective, primarily in the treatment of solid tumours, including melanoma, non-small cell lung carcinoma, and classical Hodgkin's lymphoma. The reason for this efficacy is the immunosuppressive microenvironment typical for many cancer types, directly and indirectly inhibiting effector T-cell responses. To date, three cytotoxic T-lymphocyte antigen 4 (CTLA-4) or programmed cell death protein 1 (PD-1) checkpoint inhibitors have been approved in Europe, and six in the USA. Furthermore, an increasing number of these drugs is available in the setting of clinical trials. For the optimal use of the numerous different ICIs there is an ever increasing need to identify reliable predictive biomarkers and to explore therapy-associated resistance mechanisms, which will represent the main challenge of the next years.


Effects of seasonality and moult cycle on the proliferation of nerve cells and on the labelling of ecdysone receptors in an estuarine crab.
Decapod crustaceans show proliferation of the nerve cells in the olfactory lobe throughout their lives. However, the regulation of this process is still poorly understood, since it may vary with endogenous and exogenous factors. The objective of the present investigation was to quantify the proliferation of nerve cells and number of nerve cells with ecdysone receptors in the clusters of the central olfactory system in Neohelice granulata, according to moult stages and in different seasons (summer and winter). Three injections of bromodeoxyuridine (BrdU) were administered to the crabs. Brains were sectioned by microtome and fixed on slides for immunohistochemistry with anti-BrdU and anti-EcR antibodies. The proliferation of nerve cells was higher in winter than in summer, probably because in winter the crabs do not breed and the premoult and postmoult periods are longer. Crabs in postmoult exhibited more BrdU-labelled cells than crabs in premoult or intermoult in winter, because of a greater number of mitoses related to an increase in body size and addition of olfactory receptor neurons. The number of EcR-labelled cells was higher in premoult than in postmoult or intermoult in winter. The proliferation of nerve cells is regulated seasonally and according to moult stages.


Designing Drug Trials for Frailty: ICFSR Task Force 2018.
To reduce disability and dependence in older adults, frailty may represent an appropriate target for intervention. While preventing frailty through lifestyle interventions may be the optimal public health approach for many population groups, pharmacological approaches will likely be needed for individuals who meet frailty criteria or who have comorbid conditions that contribute to and complicate the frailty syndrome, and for those who are not compliant with lifestyle interventions. Barriers to successful development of drug treatments for frailty include variability in how the frailty syndrome is defined, lack of agreement on the best diagnostic tools and outcome measures, and the paucity of sensitive, reliable, and validated biomarkers. The International Conference on Frailty and Sarcopenia Research Task Force met in Miami, Florida, on February 28, 2018, to consider the status of treatments under development for frailty and discuss potential strategies for advancing the field. They concluded that at the present time, there may be a more productive regulatory pathway for adjuvant treatments or trials targeting specific functional outcomes such as gait speed. They also expressed optimism that several studies currently underway may provide the insight needed to advance drug development for frailty.


[Effect of the antitumor antibiotic actinoxanthine on cells cultured in vitro].
Significant changes in the nucleus structure, complete suppression of the mitotic activity, markedly decreased synthesis of RNA (by 70--80 per cent according to incorporation of 3H-uridine) and decreased levels of DNA (by 40 per cent according to olivomycin binding) were observed in the fibroblasts cultivated in vitro due to exposure to actinoxanthine in an amount of 50 microgram/ml. The data indicate direct damaging effect of the drug on the cell chromatin. The above nuclear changes were also observed after a short-term exposure of the cells to the drug (up to 5 minutes). Still, they became evident only after the subsequent incubation of the cells in a pure culture medium for at least 15 minutes. No such changes in the nucleus structure were detected when after the 5-minute exposure to actinoxanthine the cells were exposed to trypsin for 3 minutes. When the time of exposure to actinoxanthine was longer (15 minutes and higher), trypsin suppressed the manifestation of the above nuclear changes. The two-stage mechanism of the damaging effect of actinoxanthine on the chromatin of the cells cultivated in vitro is discussed. The damaging effect of actinoxanthine on the cells begins from binding of the drug with the cell membrane. After that a short incubation period follows and then the characteristic changes in the nucleus structure appear.


Analysis of Subcellular Prefoldin 1 Redistribution During Rabies Virus Infection.
Rabies virus (RABV) is one of the old deadly zoonotic viruses. It attacks the central nervous system and causes acute encephalitis in humans and animals. Host factors are known to be essential for virus infection and replication in cells. The identification of the key host factors required for RABV infection may provide important information on RABV replication and may provide new potential targets for RABV drug discovery. This study aimed to investigate the change in the subcellular distribution and expression of the host protein Prefoldin subunit 1 (PFDN1) in RABV-infected cells and the viral expression of plasmids in the transfected cells. Mouse Neuro-2a (N2a) cells were infected by RABV or transfected with the plasmids of the nucleoprotein (N) and/or phosphoprotein (P) gene of RABV. The subcellular distribution of PFDN1 was analyzed by confocal microscopy, and the transcription levels of PFDN1 in the N and/or P gene of the RABV-transfected or RABV-infected N2a cells were assessed via real-time quantitative polymerase chain reaction. Confocal microscopy showed that PFDN1 was colocalized with the N protein of RABV in the infected N2a cells and was mainly recruited to the characteristic Negri-Body-Like (NBL) structures in the cytoplasm, as well as the cotransfection of the N and P genes of RABV. The transcription of PFDN1 in the RABV-infected N2a cells was upregulated, whereas the transfection of the N and/or P genes did not result in the upregulation of PFDN1. The results of this work demonstrated that the subcellular distribution of PFDN1 was altered in the RABV-infected N2a cells and colocalized with the N protein of RABV in the NBL structures.


Interaction between Pseudomonas and CXC chemokines increases risk of bronchiolitis obliterans syndrome and death in lung transplantation.
Pseudomonas aeruginosa is the most commonly isolated gram-negative bacterium after lung transplantation and has been shown to up-regulate glutamic acid-leucine-arginine-positive (ELR(+)) CXC chemokines associated with bronchiolitis obliterans syndrome (BOS), but the effect of pseudomonas on BOS and death has not been well defined. To determine if the influence of pseudomonas isolation and ELR(+) CXC chemokines on the subsequent development of BOS and the occurrence of death is time dependent. A three-state model was developed to assess the likelihood of transitioning from lung transplant (state 1) to BOS (state 2), from transplant (state 1) to death (state 3), and from BOS (state 2) to death (state 3). This Cox semi-Markovian approach determines state survival rates and cause-specific hazards for movement from one state to another. The likelihood of transition from transplant to BOS was increased by acute rejection, CXCL5, and the interaction between pseudomonas and CXCL1. The pseudomonas effect in this transition was due to infection rather than colonization. Movement from transplant to death was facilitated by pseudomonas infection and single lung transplant. Transition from BOS to death was affected by the length of time in state 1 and by the interactions between any pseudomonas isolation and CXCL5 and aspergillus, either independently or in combination. Our model demonstrates that common post-transplantation events drive movement from one post-transplantation state to another and influence outcomes differently depending upon when after transplantation they occur. Pseudomonas and the ELR(+) CXC chemokines may interact to negatively influence lung transplant outcomes.


[Displacement and tissue remodeling of temporomandibular joint disc].
Sounding takes the highest prevalence of the signs of temporomandibular disorders (TMD). The well accepted theory of the mechanism for temporomandibular joint (TMJ) sounding is the internal derangement typically characterized by disc displacement. However, according to literature, there are approximately one third of asymptomatic joints in population had disc displacement, and, on the other hand, there are one fourth of TMJ sounding patients had not signs or very limited signs of disc displacement. Replacing the displaced disc to the normal position via methods like surgical operation did not achieve satisfactory long-term outcomes. In this review, we discuss and analyze the possible remodeling of the joint disc displacement diagnosed with imaging based on the anatomy and pathophysiology.


The public health response to disasters in the 21st century: reflections on Hurricane Katrina.
Ten years ago, in 1996, the author published a commentary on disasters, the environment, and public health, reviewing progress in the field. Despite many advances, significant events have occurred during the intervening decade, including the September 11, 2001, terrorist attacks and the 2005 Hurricane Katrina disaster. The recent lessons from Hurricane Katrina indicate that public health professionals still need to do more to protect the public in times of national disasters. Since recurring disasters will continue to adversely affect human health, public health providers and others involved with disaster management should again reflect on the importance of this issue and the need for action. Such action includes key public health professionals being present and actively involved in the field before and immediately following disaster impact.


Incremental Value of Ga-68 Prostate-Specific Membrane Antigen-11 Positron-Emission Tomography/Computed Tomography Scan for Preoperative Risk Stratification of Prostate Cancer.
Prostate cancer (PC) is the second-most common cause of cancer.68Ga-prostate-specific membrane antigen (PSMA)-11 positron-emission tomography/computed tomography (PET/CT) scan help in accurate staging of PC owing to its high PSMA avidity and specificity. The aim of this prospective observational study was to determine the incremental value of Ga-68 PSMA-11 PET/CT over multiparametric magnetic resonance imaging (mpMRI) in the locoregional staging of intermediate- and high-risk PC using histopathology from radical prostatectomy specimens as a gold standard. This was a prospective study, including 35 patients with biopsy-proven prostate carcinoma. All the patients underwent whole-body Ga-68 PSMA-11 PET/CT scans along with mpMRI including a dedicated pelvic imaging protocol within a time window of ± 10 days. The reference standard was based on histopathological results, postprostatectomy. All 35 patients showed Ga-68 PSMA-11-avid disease, of which 29 underwent radical prostatectomy, one underwent radiation therapy, and five did not undergo surgery owing to metastases. A total of 52 PC lesions were detected in 29 patients on histopathology. Of 52 lesions, 29 lesions were identified in prostate parenchyma and 23 were extraprostatic lesions on histopathology. Ga-68 PSMA-11 PET/CT detected a total of 45 lesions, of which 29 lesions were located within the prostate parenchyma and 16 were representative of extraprostatic lesions. mpMRI detected a total of 36 lesions, of which 29 lesions were located within the prostate parenchyma and seven were representative of extraprostatic lesions. The overall sensitivity of 68Ga-PSMA PET/CT and mpMRI in the detection of lesions was 86.2% and 68.6%, respectively. However, the overall specificity was 94.7% and 89.1% for 68Ga-PSMA and mpMRI, respectively. Ga-68 PSMA-11 PET/CT provided superior locoregional preoperative staging of PC as compared to mpMRI in intermediate- and high-risk PC patients.


Visible-Light-Induced Synthesis of Carbazoles by in Situ Formation of Photosensitizing Intermediate.
A visible-light-induced synthesis of N-H carbazoles from easily accessible 2,2'-diaminobiaryls in the absence of any external photosensitizer is reported. The process only requires tBuONO and natural resources, visible light, and molecular oxygen for the synthesis of N-H carbazoles. Experimental and computational studies support that the in situ formation of a visible-light-absorbing photosensitizing intermediate, benzocinnoline N-imide, is responsible for the activation of triplet molecular oxygen to singlet oxygen that, in turn, promotes the synthesis of carbazole.


Proliferative activity in clinically healthy oral mucosa exposed to tobacco smoking and alcohol: a longitudinal study using the agNOR staining technique.
To evaluate cell proliferation in clinically healthy oral mucosa exposed to smoking and alcohol carcinogens over a period of 24 months using the AgNOR staining technique. Sixty patients were initially evaluated: 17 were control individuals, 25 were smokers and 18 were smokers and alcohol drinkers. Fifty-two of these patients were reevaluated. Specimens for cytology were obtained from swabs of lower lip mucosa, border of the tongue and floor of the mouth and underwent AgNOR staining for evaluation of mean number and mean area of AgNOR dots per nucleus and percentage of nuclei with > 3 and > 5 AgNOR dots. Student t and Kruskal-Wallis tests were used to compare values obtained. A statistically significant increase was found in mean number of AgNOR dots per nucleus in 2 groups. One group showed a tendency toward increase of these values. The results of the longitudinal evaluation (Kruskal-Wallis test) revealed a statistically significant difference in number and area of AgNOR dots in the cells of the lower lip. The increase of the variables suggests that the longitudinal evaluation of changes in cell proliferation in individuals exposed to smoking and alcohol carcinogens may be a useful monitoring tool.


Paradoxical Tumor Necrosis Factor-Alpha (TNF-α) Inhibitor-Induced Psoriasis: A Systematic Review of Pathogenesis, Clinical Presentation, and Treatment.
Tumor necrosis factor-alpha (TNF-α) inhibitors have been shown to be well tolerated among patients with rheumatoid arthritis, inflammatory bowel disease, and psoriasis. Meanwhile, more recently, clinical practice and research efforts have uncovered increasing cases of psoriatic lesion development tied to initiating treatment with a TNF-α inhibitor. The underlying mechanisms associated with this occurrence have yet to be fully elucidated. A review and analysis of cases of paradoxical psoriasis currently published in the literature is warranted. In addition, exploring possible mechanisms of action and potential treatment options associated with favorable outcomes is much needed. A systematic literature review was performed utilizing PubMed and Google Scholar databases (1992-present), in which 106 cases of paradoxical psoriasis were reviewed. The most common morphology developed was plaque psoriasis vulgaris. There was a female predominance (61.3%), and the most common underlying autoimmune disease was rheumatoid arthritis (45.3%). In addition, the most commonly associated drug with the onset of psoriatic lesions was infliximab (62.3%). Furthermore, the findings suggest that the most well-supported mechanism of action involves the uncontrolled release of interferon-alpha (IFN-α) from plasmacytoid dendritic cells (pDCs) after TNF-α inhibition. While TNF-α inhibitors have been shown to have great benefits to patients with rheumatologic diseases, cases of paradoxical psoriasis demonstrate the importance of close monitoring of patients on TNF-α inhibitors to allow for early recognition, treatment, and potentially change to a different mechanism of action of the medication used to prevent further progression of the inflammatory lesions.


[Carvedilol effectiveness for left ventricular-insufficient patients with Duchenne muscular dystrophy].
To evaluate the efficacy of carvedilol for left ventricular dysfunction in Duchenne muscular dystrophy (DMD), we enrolled 8 patients with DMD who had elevated plasma atrial natriuretic peptide (ANP) or brain natriuretic peptide (BNP), and a low ejection fraction (EF < 40%) in echocardiography. Written informed consent was obtained from all of them. Four agreed to be treated with oral carvedilol 0.3125-1.25 mg/day (10.1-40.3 micrograms/kg/day) for 6 months (treated group). The others served as the controls (untreated group). In both groups, we evaluated clinical symptoms, plasma ANP, BNP and EF before, 3 and 6 months after the trial, and iodine-123 metaiodobenzylguanidine (123I-MIBG) imaging at 6 month interval. Parameters in the treated and untreated groups before respectively were ANP, 83.8 +/- 17.5 and 89.5 +/- 44.4 pg/ml (mean +/- SEM); BNP, 169.0 +/- 46.2 and 186.3 +/- 61.8 pg/ml; EF, 24.0 +/- 2.2 and 16.5 +/- 1.9%; Heart/Mediastrinum ratio of the 123I-MIBG delayed image, 1.65 +/- 0.08 and 1.6 +/- 0.10; and Washout rate, 46.5 +/- 8.6 and 41.4 +/- 7.8. These values did not change significantly before and 6 months after for either group. Clinical symptoms also did not change in either group. Carvedilol therapy did not change the left ventricular dysfunction in DMD.


Erlotinib-related bilateral anterior uveitis.
The authors report the case of a 68-year-old woman with secondary adenocarcinoma of the lungs from an unknown primary. Erlotinib was started which produced symptoms suggestive of uveitis. Erlotinib was stopped and restarted a month later at a lower dose, which resulted in severe bilateral anterior uveitis. The uveitis settled after stopping erlotinib and treatment with topical steroids and cycloplegics. To the best of the authors' knowledge, this is the first case of erlotinib-related anterior uveitis.


Mycobacterial Spindle Cell Pseudotumor (MSP): A Case Report.
Mycobacterial spindle cell pseudotumor (MSP) is a rare proliferation of spindle-shaped histiocytes that occurs most frequently in lymph nodes but has also been documented in the skin, soft tissue, abdomen, and other sites. These lesions contain acid-fast mycobacteria, most commonly Mycobacterium avium complex. Fewer than 10 cases of cutaneous MSPs have been published, and most have occurred in immunocompromised patients, either due to human immunodeficiency virus (HIV) infection or immunosuppressive medications. The differential diagnosis includes Kaposi's sarcoma and other spindle cell neoplasms, which can be distinguished based on histology and special stains. We present the case of a 76-year-old man with HIV infection who presented with a diffuse rash on his arms and legs. A pretibial biopsy was performed and revealed tubercular MSP.


Pain-relieving effectiveness, quality of life and tolerability of repeated capsaicin 8% patch treatment of peripheral neuropathic pain in Scandinavian clinical practice.
Clinical trials have demonstrated the efficacy and safety of the capsaicin 8% patch in patients with peripheral neuropathic pain (PNP); however, few studies have assessed this treatment in a clinical practice. To determine whether treatment and re-treatment with the capsaicin 8% patch reduce PNP intensity in clinical practice. Three non-interventional, observational studies were concurrently conducted in Denmark, Norway and Sweden. Patients with probable or definite PNP received one or two treatments with the capsaicin 8% patch according to usual clinical practice. All analyses were performed on combined data. Overall, 382 and 181 patients received treatment and re-treatment, respectively, with the capsaicin 8% patch. At the group level, a significant reduction in mean level of 'usual pain' intensity (Numerical Pain Rating Scale) over the last 24 h' score was observed from baseline to Weeks 2 through 8 [-1.05 (95% confidence interval: -1.27, 0.82); p < 0.001] with 28% and 31% of patients reporting a ≥30% reduction in pain after first treatment and re-treatment, respectively. Improvements in health-related quality of life (EQ-5D-3L index) and overall health status (Patient Global Impression of Change) were observed early (Week 1) and throughout the treatment periods. Most application site reactions subsided within a week after treatment. Following treatment and re-treatment, 57% and 71% of patients, respectively, were willing to undergo further treatment with the capsaicin 8% patch. In Scandinavian clinical practice, capsaicin 8% patch treatment was associated with significant reductions in pain intensity and was well tolerated with over half of patients willing to undergo re-treatment.


Isolation of cDNAs encoding guanine nucleotide-binding protein beta-subunit homologues from maize (ZGB1) and Arabidopsis (AGB1).
We have isolated cDNAs from maize (ZGB1) and Arabidopsis (AGB1) encoding proteins homologous to beta subunits of guanine nucleotide-binding protein (G protein). The predicted ZGB1 and AGB1 gene products are 76% identical to each other and 41% or more identical to animal G protein beta subunits. Both predicted proteins contain seven repeats of the so-called "WD-40" motif, where WD is Trp-Asp. RNA blot analysis indicates that ZGB1 mRNA is present in the root, leaf, and tassel and that AGB1 mRNA is expressed in the root, leaf, and flower. DNA blot hybridizations indicate that maize and Arabidopsis genomes contain no other genes that are highly similar to ZGB1 and AGB1, respectively, suggesting that the newly isolated G protein beta-subunit homologues are likely to have unique functions. Furthermore, these G protein beta-subunit homologues are conserved among other plant species and may play important role(s) in plant signaling.


Extrapancreatic organ impairment during acute pancreatitis induced by bile-pancreatic duct obstruction. Effect of N-acetylcysteine.
Multiple organ failure is frequently associated with acute pancreatitis (AP). Our aim was to study pulmonary, hepatic and renal complications developed in the course of AP experimentally induced in rats by bile-pancreatic duct obstruction (BPDO), differentiating the complications caused by AP itself, from those directly caused by bile duct obstruction (BDO), after ligating the choledocus. N-acetylcysteine (NAC) was administered as a therapeutic approach. Myeloperoxidase activity revealed neutrophil infiltration in lungs from 12 h after BDO, even if AP was not triggered. Lactate dehydrogenase (LDH) activity indicated hepatocyte death from 48 h after BDO, and from 24 h following BPDO-induced AP onwards, an effect delayed until 48 h by NAC treatment. Rats with single cholestasis (BDO) and rats with BPDO-induced AP showed a significant increase in plasma aspartate aminotransferase (AST), alanine aminotransferase (ALT) and bilirubin concentration from 12 h onwards, whose values were reduced by NAC treatment at early BPDO. No renal failure was found during 120 h of bile-pancreatic obstruction. Our results showed lung and liver impairment as a result of BDO, even if AP does not develop. Pancreatic damage and extrapancreatic complications during AP induced by BPDO were palliated by NAC treatment.


Surface kinematic and depth-resolved analysis of human vocal folds in vivo during phonation using optical coherence tomography.
The human vocal fold (VF) oscillates in multiple vectors and consists of distinct layers with varying viscoelastic properties that contribute to the mucosal wave. Office-based and operative laryngeal endoscopy are limited to diagnostic evaluation of the VF epithelial surface only and are restricted to axial-plane characterization of the horizontal mucosal wave. As such, understanding of the biomechanics of human VF motion remains limited. Optical coherence tomography (OCT) is a micrometer-resolution, high-speed endoscopic imaging modality which acquires cross-sectional images of tissue. Our study aimed to leverage OCT technology and develop quantitative methods for analyzing the anatomy and kinematics of in vivo VF motion in the coronal plane. A custom handheld laryngeal stage was used to capture OCT images with 800 A-lines at 250 Hz. Automated image postprocessing and analytical methods were developed. Novel kinematic analysis of in vivo, long-range OCT imaging of the vibrating VF in awake human subjects is reported. Cross-sectional, coronal-plane panoramic videos of the larynx during phonation are presented with three-dimensional videokymographic and space-time velocity analysis of VF motion. Long-range OCT with automated computational methods allows for cross-sectional dynamic laryngeal imaging and has the potential to broaden our understanding of human VF biomechanics and sound production.


Characterization of left ventricular opacification using sonicated serum albumin in patients with dilated cardiomyopathy and myocardial infarction.
To elucidate whether the mode of left ventricular opacification using sonicated serum albumin (SSA) is dependent upon the severity of left ventricular dysfunction, SSA was administered intravenously to 26 patients with dilated cardiomyopathy, 24 patients with anteroseptal myocardial infarction, and 9 normal control subjects. The left ventricular inflow pattern in echocardiograms on the apical 4-chamber view was classified into 2 types: straight or whirling. The ratio of left ventricular opacified area to left ventricular end-diastolic area, called the percent left ventricular effective fraction (%LVEF), was also calculated. The inflow pattern was straight in all normal control subjects and 9 myocardial infarction patients, whereas 15 myocardial infarction and all dilated cardiomyopathy patients showed the whirling pattern. Percent LVEF was significantly smaller in patients with dilated cardiomyopathy (45 +/- 22%, p < 0.0001) and myocardial infarction (65 +/- 14%, p < 0.001) than in normal control subjects (84 +/- 7%). The area that was not opacified was observed only in the infarcted area in cases of myocardial infarction, and over wide regions in cases of dilated cardiomyopathy. In addition, there were significant correlations between %LVEF and ejection fraction or peak filling rate. These findings indicate that contrast echocardiography using SSA can reflect sensitively the severity of left ventricular dysfunctions and detect the regions involved in patients with dilated cardiomyopathy and myocardial infarction.


The USDA Automated Multiple-Pass Method accurately estimates group total energy and nutrient intake.
The imperative to address the national obesity epidemic has stimulated efforts to develop accurate dietary assessment methods suitable for large-scale applications. This study evaluated the performance of the USDA Automated Multiple-Pass Method (AMPM), the computerized dietary recall designed for the National Health and Nutrition Examination Survey dietary survey, and 2 epidemiological methods [the Block food-frequency questionnaire (Block) and National Cancer Institute's Diet History Questionnaire (DHQ)] using doubly labeled water (DLW) total energy expenditure (TEE) and 14-d estimated food record (FR) absolute nutrient intake as criterion measures. Twenty highly motivated, normal-weight-stable, premenopausal women participated in a free-living study that included 2 unannounced AMPM recalls and completion of the Block and DHQ. AMPM and FR total energy intake (TEI) did not differ significantly from DLW TEE [AMPM: 8982 +/- 2625 kJ; FR: 8416 +/- 2217; DLW: 8905 +/- 1881 (mean +/- SD)]. Conversely, the questionnaires underestimated TEI by approximately 28% (Block: 6365 +/- 2193; DHQ: 6215 +/- 1976; P < 0.0001 vs. DLW). Pearson correlation coefficients for DLW TEE with each dietary method TEI showed a stronger linear relation for AMPM (r = 0.53; P = 0.02) and FR (r = 0.41; P = 0.07) than for the Block (r = 0.25; P = 0.29) and DHQ (r = 0.15; P = 0.53). Most mean absolute FR nutrient intakes were closely approximated by the AMPM but were significantly underestimated by the questionnaires. In highly motivated premenopausal women, the AMPM provides valid measures of group total energy and nutrient intake whereas the Block and DHQ yield underestimations.


Comparison of permanent and nonpermanent staple line buttressing materials for linear gastric staple lines during laparoscopic Roux-en-Y gastric bypass.
Several publications have suggested that staple line buttressing might decrease staple line bleeding, increase burst pressure, and decrease the likelihood of acute failure resulting in leak. Currently, permanent and nonpermanent options are available. However, concern has been raised about the permanent buttress material and its potential for delayed strip expulsion. This study analyzed our experience with 3 different buttressing materials for creating the gastric division during laparoscopic Roux-en-Y gastric bypass. From July 5, 2001 to May 30, 2007, 1451 consecutive patients underwent laparoscopic gastric bypass with buttressing material used for the stapled creation of the gastric pouch. Peristrips Dry (PSDs), permanent bovine pericardial strips, were used in 926 cases from July 5, 2001 to October 11, 2005. Seamguards, a synthetic bioabsorbable product, were used in 145 cases from November 2, 2004 to July 18, 2006, and PSD Veritas, remodelable, nonpermanent bovine pericardial strips, were placed in 380 patients from October 11, 2005 to May 30, 2007. All products were applied to the 60-mm-long, 3.5-mm cartridges of the EndoGIA II stapler. The ease of use, operative complications, visual bleeding, and postoperative leaks were recorded. The patient characteristics were comparable for all groups. All products were easy to load on the stapler, and no operative complications related to the use of the buttress materials occurred. The incidence and severity of staple line bleeding was not specifically calculated but was visually noted to be minimal in all cases. Of the 3 groups, 4 contained leaks occurred in the Seamguards group, and all were successfully managed nonoperatively. No acute leaks were discovered in the PSD or PSD Veritas groups. This difference was statistically significant (p <.001). Neither the PSDs or PSD Veritas group exhibited staple line complications. However, 4 leaks occurred in the patients who had Seamguards incorporated into their gastric pouch linear staple lines.


Occipital artery arising from the anterior aspect of the internal carotid artery identified by three-dimensional computed tomography angiography.
Variation of the branches of the external carotid artery (ECA) is well known, but it is extremely rare for the occipital artery (OA) to arise from the internal carotid artery (ICA). A 87-year-old man was found to have this anatomical variation on the right side by threedimensional computed tomography angiography for vascular mapping of the carotid arteries before superselective intra-arterial catheterization for advanced tongue cancer. Imaging showed the OA arose from the anterior aspect of the right ICA with the origin located 8.8 mm distal from the carotid bifurcation. The inner diameter of the origin of the OA was 2.1 mm and the angle between the OA and the ICA was 62 degrees. It is important to recognize this anatomic variation of the branches of the ECA before head and neck microsurgical reconstruction or superselective intra-arterial chemotherapy for oral cancer.


Synthesis and estrogenic activity of bisphenol a mono- and di-beta-D-glucopyranosides, plant metabolites of bisphenol A.
The syntheses and characterization of bisphenol A mono- and di-beta-D-glucopyranosides were undertaken to confirm that these compounds are major plant metabolities of bisphenol A (BPA) and to allow an assessment of their estrogenicity. Synthesis involved the glucosidation of unprotected BPA with glucose penta-acetate with phosphorus oxychloride as catalyst. The estrogenic activity of BPA and its mono- and di-beta-D-glucopyranosides were measured with an enzyme-linked immunosorbent assay (ELISA)-based estrogen receptor competitive binding assay and with a yeast two-hybrid assay adapted to a chemiluminescent reporter gene (for beta-galactosidase). Both methods showed that the estrogenicity of BPA was eliminated by formation of the di-glucoside, but whereas the ELISA-based method indicated that reduced activity remained in the monoglucoside, the yeast two-hybrid method showed the monoglucoside to be inactive. Presumably these results reflect the more complex interactions of test compound and cellular components required to demonstrate estrogenicity in the yeast two-hybrid assay. As these processes parallel those in mammalian cells, the yeast two-hybrid method is likely to be the more realistic assay. The uptake and metabolism of BPA by plants offers the possibility of phytoremediation of contaminated water, but also provides an additional route for the compound to enter the human food chain.


High-Resolution Photonic Force Microscopy Based on Sharp Nanofabricated Tips.
Although near-field imaging techniques reach sub-nanometer resolution on rigid samples, it remains extremely challenging to image soft interfaces, such as biological membranes, due to the deformations induced by the probe. In photonic force microscopy, optical tweezers are used to manipulate and measure the scanning probe, allowing imaging of soft materials without force-induced artifacts. However, the size of the optically trapped probe still limits the maximum resolution. Here, we show a novel and simple nanofabrication protocol to massively produce optically trappable quartz particles which mimic the sharp tips of atomic force microscopy. Imaging rigid nanostructures with our tips, we resolve features smaller than 80 nm. Scanning the membrane of living malaria-infected red blood cells reveals, with no visible artifacts, submicron features termed knobs, related to the parasite activity. The use of nanoengineered particles in photonic force microscopy opens the way to imaging soft samples at high resolution.


Oesophageal intubation and ventilation as initial airway support of newborn infant with tracheal agenesis.
Tracheal agenesis is a rare congenital airway anomaly which presents as an airway emergency at birth. We report a case of late premature Chinese infant with tracheal agenesis type II (by Floyd's classification) who presented with severe respiratory distress at birth. He had multiple failed attempts at intubations with accidental oesophageal intubation and ventilation. Tracheal agenesis with tracheo-oesophageal fistula was suspected from an emergency optical laryngoesophagoscopy done. The infant was subsequently stabilized on oesophageal ventilation. The diagnosis was confirmed on CT scan and parents were counseled regarding the poor outcome and decided for withdrawal at day 7 of life.


[Cytokines in rheumatoid arthritis: new therapeutic possibilities].
The ingress of inflammatory leukocytes into the synovium is important for the pathogenesis of rheumatoid arthritis. Soluble inflammatory mediators regulate the inflammatory, chemotactic, adhesive, angiogenic events, as well as osteopenia associated with this disease. In this review authors discuss the role of a number of inflammatory mediators, such as cytokines, chemokines and growth factors in these processes. The outcome of arthritis is highly dependent on the imbalance between pro-inflammatory and anti-inflammatory mediators. Cytokine-related research also has important clinical relevance. Many of these proteins are detectable in the serum of rheumatoid patients and may eventually serve as useful laboratory markers of disease activity. Antirheumatic therapy currently used for the treatment of rheumatoid arthritis is often limited. Therefore, we need to consider alternative therapeutic regimens, such as the inhibition of cytokines and other soluble mediators, in order to prevent severe joint destruction. While there are many complex interactions involving cytokine networks and cascades in the arthritic joint, there are promising attempts to eliminate a single cytokine in clinical trials, such as ablation of tumor necrosis factor-alpha. Hopefully, the study of cytokines and their networks will lead to specific immunomodulatory therapies that will benefit rheumatoid patients by preventing joint destruction.


A natural human monoclonal antibody targeting Staphylococcus Protein A protects against Staphylococcus aureus bacteremia.
Staphylococcus aureus can cause devastating and life-threatening infections. With the increase in multidrug resistant strains, novel therapies are needed. Limited success with active and passive immunization strategies have been attributed to S. aureus immune evasion. Here, we report on a monoclonal antibody, 514G3, that circumvents a key S. aureus evasion mechanism by targeting the cell wall moiety Protein A (SpA). SpA tightly binds most subclasses of immunoglobulins via their Fc region, neutralizing effector function. The organism can thus shield itself with a protective coat of serum antibodies and render humoral immunity ineffective. The present antibody reactivity was derived from an individual with natural anti-SpA antibody titers. The monoclonal antibody is of an IgG3 subclass, which differs critically from other immunoglobulin subclasses since its Fc is not bound by SpA. Moreover, it targets a unique epitope on SpA that allows it to bind in the presence of serum antibodies. Consequently, the antibody opsonizes S. aureus and maintains effector function to enable natural immune mediated clearance. The data presented here provide evidence that 514G3 antibody is able to successfully rescue mice from S. aureus mediated bacteremia.


Activated charcoal based diffusive gradients in thin films for in situ monitoring of bisphenols in waters.
Widespread use of bisphenols (BPs) in our daily life results in their elevated concentrations in waters and the need to study their environmental impact, which demands reliable and robust measurement techniques. Diffusive gradients in thin films (DGT) is an in situ passive sampling approach which provides time-integrated data. In this study we developed a new methodology, based on DGT with activated charcoal (AC) as a binding agent, for measuring three BPs (BPA, BPB, and BPF) which incorporated and tested its performance characteristics. Consistent elution efficiencies were obtained using methanol when concentrations of BPs were low and a methanol-NaOH mixture at high concentrations. The diffusion coefficients of BPA, BPB, and BPF in the diffusive gel, measured using an independent diffusion cell, were 5.03 × 10(-6), 5.64 × 10(-6), and 4.44 × 10(-6) cm(2) s(-1) at 25 °C, respectively. DGT with an AC binding gel had a high capacity for BPA, BPB, and BPF at 192, 140, and 194 μg/binding gel disk, respectively, and the binding performance did not deteriorate with time, up to 254 d after production. Time-integrated concentrations of BPs measured in natural waters using DGT devices with AC gels deployed in situ for 7 d were comparable to concentrations measured by an active sampling method. This study demonstrates that AC-based DGT is an effective tool for in situ monitoring of BPs in waters.